tbuckley/cabot-search huggingface dataset:
Time to first treatment and optimal adjuvant treatment strategy in patients with resectable gastric cancer pathologically upstaged to lymph node–positive disease.
Authors: Pranay Shah Ajay, Caitlin Sok, Subir Goyal, Jeffrey M. Switchenko, Felipe Maegawa, Theresa Wicklin Gillespie, Chrystal M Paulos, David A. Kooby, Timothy Kennedy, Mihir Maheshkumar Shah
Journal: Journal of Clinical Oncology (2023)

473 Background: Treatment strategies in resectable gastric cancer (GC) patients include perioperative chemotherapy (PEC), postoperative chemoradiation therapy (POCR), and postoperative chemotherapy (POC). Treatment delay can lead to metastases with unfavorable outcomes. We aim to identify the distribution of patients upstaged to pathologically node positive disease (pLN+) stratified by time and the optimal treatment in this cohort. Methods: We analyzed resected GC patients in the National Cancer Database (2004-2016) with clinically node negative disease (cLN-). Time from diagnosis to first definitive therapy was stratified as ≤2, &gt;2 to ≤4, and &gt;4 weeks. The distribution of patients upstaged from cLN- to pLN+ disease, the concordance between cLN- and pathologically lymph node negative (pLN-) disease based on treatment strategy, and time to first definitive therapy was analyzed. POC and POCR were compared to evaluate their effect on overall survival (OS) in patients with cLN- upstaged to pLN+ disease. Kaplan-Meier test, log-rank test, multivariable Cox proportional hazards analysis (MVA) were performed. Results: Of the 4,828 gastric cancer patients with cLN- disease, 514 (10.65%) patients received PEC and 4,314 (89.35%) patients received upfront surgery followed by POCR/POC. Distribution of patients stratified by time between diagnosis to first definitive treatment - chemotherapy (PEC) or surgery (POC/POCR), for ≤2 weeks was 9.5% vs. 33%, &gt;2 - ≤4 weeks was 28.4% vs. 24.2% and &gt;4weeks was 62% vs 42.7%, respectively. Patients upstaged from cLN- to pLN+ disease in the PEC group was 43.37%(n=206), and 70%(n=2574) in the upfront surgery group (POC/POCR). Of the 206 (43.37%) patients upstaged from cLN- to pLN+ in the PEC cohort, the upstage rate was 7.77% when chemotherapy was started within 2 weeks of diagnosis, compared to 27.67% with &gt;2 to ≤4 weeks, and 64.56% with &gt;4 weeks. Of the 2,574 (70%) patients upstaged in the upfront surgery cohort (POCR/POC), 30.61% were upstaged in ≤2 weeks, 24.95% in &gt;2 to ≤4 weeks, and 44.44% in ≥4 weeks. On MVA, patients with cLN- disease that were pLN- (POCR=766, POC=341) had no significant difference in OS when treated with POCR (HR 1.11, p=0.39) compared to POC. Patients with pLN+ (POCR=2300, POC=907) disease had an association with improved OS when treated with POCR (HR 0.78, p&lt;0.001) compared to POC. Conclusions: When resectable gastric cancer patients undergoing upfront surgery are upstaged from clinically node negative to pathologically node positive disease, postoperative chemoradiation therapy may be the optimal treatment strategy compared to postoperative chemotherapy. Clinical nodal status may not be an optimal predictor of nodal disease.
Effect of CXCL1 on the NF-κB/P300 signaling pathway and colon cancer progression.
Authors: Changhua Zhuo, Qiang Ruan, Xiangqian Zhao, Yangkun Shen, Ruirong Lin
Journal: Journal of Clinical Oncology (2023)

236 Background: The upregulated expression of CXCL1 has been validated in colorectal cancer patients. As a potential biotherapeutic target for colorectal cancer, the mechanism by which CXCL1 affects the development of colorectal cancer is not clear. Methods: Expression data of CXCL1 in colorectal cancer were obtained from the GEO database and verified using the GEPIA database and the TIMER 2.0 database. Knockout and overexpression of CXCL1 in colorectal cancer cells by CRISPR/Cas and "Sleeping Beauty" transposon-mediated gene editing techniques. Cell biological function was demonstrated by CCK-8, transwell chamber and Colony formation assay. RT-qPCR and Western Blot assays measured RNA and protein expression. Protein localization and expression were measured by immunohistochemistry and immunofluorescence. Results: Bioinformatics analysis showed significant overexpression of CXCL1 in the colorectal cancer tissues compared to normal human tissues, and identified CXCL1 as a potential therapeutic target for colorectal cancer. We demonstrate that CXCL1 promotes the proliferation and migration of colon cancer cells and has a facilitative effect on tumor angiogenesis. Furthermore, CXCL1 elevation promoted the migration of M2-tumor associated macrophages (TAMs) while disrupting the aggregation of CD4+ and CD8+ T cells at tumor sites. Mechanistic studies suggested that CXCL1 activates the NF-κB pathway. In the in vivo colon cancer transplantation tumor model, treatment with the P300 inhibitor C646 significantly inhibited the growth of CXCL1-overexpressing colon cancer. Conclusions: CXCL1 promotes colon cancer development through activation of NF-κB/P300, and that CXCL1-based therapy is a potential novel strategy to prevent colon cancer development.
Differences in genomic profiles of gastric adenocarcinoma in the US and Japan.
Authors: Masaya Nakauchi, Colin Court, Henry S. Walsh, Walid Khaled Chatila, Shoji Shimada, Santosha Vardhana, Laura H. Tang, Daniel G. Coit, Yelena Y. Janjigian, Steven Brad Maron, Geoffrey Yuyat Ku, David H. Ilson, Nikolaus Schultz, Hiroshi Matsuoka, Tetsuya Tsukamoto, Ichiro Uyama, Koichi Susa, Vivian E. Strong
Journal: Journal of Clinical Oncology (2023)

299 Background: Although epidemiological and clinical differences in gastric cancer (GC) between the US and Japan have been reported, genetic differences have not been clarified. We aimed to characterize molecular differences in GC between the two countries. Methods: We collected data between January 2010 and December 2019 from a prospectively maintained database of GC at our US and Japanese centers. After matching clinicopathological backgrounds, including age, sex, clinical T and N status, and tumor location, the genomic profiles of the primary site were compared for 58 patients in each group undergoing surgical resection and had MSK-IMPACT (MSK-Integrated Mutation Profiling of Actionable Cancer Targets), a tumor-normal next generation sequencing assay that can detect alterations in exons and select introns of 505 genes. The MSI sensor algorithm was used to assess microsatellite instability. Genomic alterations were filtered for driver variants using OncoKB, and genes were consolidated into pathways using curated pathway templates from the Cancer Genome Atlas. Results: The clinicopathological characteristics were well matched between 58 patients in each cohort. In the entire cohort, the most commonly altered genes were: TP53 (45%), ARID1A (24%), and ERBB2 (17%) in the US cohort, and TP53 (50%), ARID1A (19%), and ERBB2 (17%) in the Japanese cohort. Although KMT2D was more frequently altered in the US cohort (19% vs. 2%), the two cohorts had no significant differences in other altered genes and gene pathways. The tumor with MSI high was found more frequently in the US cohort (22.4% vs. 5.2%, p = 0.01). Among the MSI-normal tumors, the tumor mutational burden (US: 3.5 muts/Mb and Japanese: 4.1 muts/Mb) and the fraction genome altered (US: 0.37 and Japanese: 0.28) did not significantly differ between the two groups. Additionally, no genes or pathways were significantly enriched in either group. Patterns of mutual exclusivity and co-occurrence amongst genes and pathways were also similar between the two groups. Conclusions: In this original genomic comparison of US and Japanese gastric cancers, matching clinicopathological backgrounds, Japanese and US gastric cancers are remarkably similar at the genomic level, with the possible exception of MSI-high tumor that appear to be more frequent in the US.
The role of serial circulating tumor DNA for predicting clinical outcomes of chemotherapy in patients with advanced gastric cancer.
Authors: Sheehyun Kim, Yoojoo Lim, Jun-Kyu Kang, Hwang-Phill Kim, Tae-You Kim, Tae-Yong Kim
Journal: Journal of Clinical Oncology (2023)

433 Background: Serial circulating tumor DNA (ctDNA) analysis enables us to detect minimal residual disease, to estimate recurrence and to trace evolution of cancer. However, the role of ctDNA in patients with advanced gastric cancer (AGC) who received palliative chemotherapy is still unclear. We performed this study to evaluate if serial ctDNA can predict clinical outcomes of chemotherapy and propose evolutionary findings during chemotherapy. Methods: The patients with histopathologically confirmed AGC and who received palliative chemotherapy were enrolled. Serial blood sample for ctDNA sequencing were obtained at baseline (BL) (before first-line chemotherapy), after first cycle and every 2-3 months until disease progression. ctDNA sequencing was performed for all samples using the next-generation sequencing (NGS) platform with a targeted gene panel including 106 genes. Single nucleotide variants (SNVs), insertions and deletions (Indels), and copy number variants (CNVs) were identified by ctDNA sequencing while serial ctDNA were monitored by tracing changes in the variants. ctDNA clearance was defined as no detection of any kind of variants or variant allele frequency (VAF) less than 0.1%. Results: A total of 50 patients were registered and 248 samples were collected. Median age was 62. HER2-positive GC were 5 (10.0%) and 49 received fluoropyrimidine plus platinum (1 did not receive chemotherapy). Response rate and median progression-free survival (PFS) were 42.9% and 10.7 months (95% CI, 7.9-13.6). Among 40 who were available for BL ctDNA, patients who were detected with ctDNA variant (D group) were 21 (52.5%). TP53 mutation was the most frequently observed genetic alteration in BL ctDNA (76.2%) and median copy numbers of ERBB2 in HER2-positive GC were 28 (range 2-42). D group were more frequently observed in tubular or papillary adenocarcinoma than in poorly cohesive carcinoma (69.0% vs. 9.1%, p = 0.001). Patients who were not detected with any kind of ctDNA variant (ND group) showed a trend in longer PFS, compared to D group, however it was not significant (10.5 vs 7.9 months, p = 0.29). In serial analysis during first-line chemotherapy, ctDNA clearance was observed in 14 (70.0%) out of 20 in D group. Patients with ctDNA clearance showed significantly longer PFS, compared with patients without ctDNA clearance (9.8 vs. 3.6 months, p &lt; 0.001). Among 32 patients who had disease progression, increased VAF or re-development of previous BL ctDNA variants were observed in 16 (50.0%). Increased VAF or re-development of BL ctDNA were detected in 2.1 months earlier than clinical or radiologic deterioration. Conclusions: Serial ctDNA could predict clinical outcomes of chemotherapy and detect disease progression earlier than clinical or radiological findings in AGC. Further study for serial ctDNA is needed to find out the resistant mechanism and evolutionary process in cancer.
Adjuvant gemcitabine+S1 as adjuvant therapy for resectable pancreatic cancer: A real-world experience in a single-center retrospective study.
Authors: Hsin-Chen Lin, Yu-Hsuan Shih
Journal: Journal of Clinical Oncology (2023)

673 Background: Current clinical guidelines recommended adjuvant chemotherapy for all resectable pancreatic cancer after operation. The treatment choices included Gemcitabine monotherapy, S1 monotherapy, Gemcitabine+Capecitabine or mFOLFIRINOX. However, the role of Gemcitabine+S1 combination as adjuvant chemotherapy was not clear. We aimed to investigate the benefit of adjuvant chemotherapy with Gemcitabine+S1 in resectable pancreatic cancer. Methods: We retrospectively reviewed the medical records of patients with resectable pancreatic cancer who underwent curative surgery and adjuvant treatments at Taichung Veterans General Hospital (Taichung, Taiwan) between January 2014 and July 2021. The clinical characteristics and outcomes were analyzed. Results: A total of 102 patients received operation were analyzed. 73 patients received adjuvant chemotherapy, including 35 patients received Gemcitabine+S1 combination. Median follow-up period was 22.7 months. The disease-free survival (DFS) and overall survival (OS) among patients received Gemcitabine+S1 combination were 15.5 months and 32.8 months, respectively. Compared with Gemcitabine monotherapy, there was a trend of superior DFS (10.5 months in Gemcitabine monotherapy, p = 0.071), but no OS benefits (23.1 months, p = 0.441) with Gemcitabine+S1 combination. When focusing on more advanced disease status (stage II and III), the Gemcitabine+S1 combination had statistically significant longer DFS (14.7 months vs. 8.6 months; p = 0.015) and OS (30.3 months vs. 21.7 months; p = 0.036), compared with Gemcitabine monotherapy. Conclusions: In our retrospective study, Gemcitabine+S1 combination could be another choice for resectable pancreatic cancer, especially in more advanced disease (stage II and III). Further result from prospective study (JSAP-04) is pending.
The impact of claudin-18.2 expression in patients with advanced gastric cancer treated with nivolumab.
Authors: Toru Kadono, Hirokazu Shoji, Hidekazu Hirano, Natsuko Okita Okita, Satoru Iwasa, Atsuo Takashima, Ken Kato
Journal: Journal of Clinical Oncology (2023)

439 Background: Claudin-18.2 (CLDN 18.2) is the components of tight junction and one of the therapeutic targets in advanced gastric cancer (AGC). It has been reported that the tumor microenvironment in CLDN18.2 high AGC contains more PD-1 negative CD8+ T cells than in CLDN18.2 low, which may make anti-PD-1 antibodies less effective. However, the data on the association between CLDN18.2 expression and prognosis in patients with AGC treated with nivolumab (NIVO) is limited. Methods: Patients who received NIVO monotherapy as third- or later-line treatment (NIVO group) and those who received only fluoropyrimidine, platinum and taxanes (non-NIVO group) at our hospital between 2015 and 2019 were enrolled. High CLDN18.2 expression was defined as ≥40% positive tumor cells with moderate to strong membranous staining on immunohistochemistry. Overall survival (OS) and progression-free survival (PFS) were compared according to CLDN18.2 expression and combined positivity score (CPS). Results: There were 71 and 50 patients in the NIVO and non-NIVO groups, respectively. Patient characteristics at first-line chemotherapy in the NIVO/non-NIVO groups were median age 67 (range, 34-83)/64.5 (29-80) years; performance status 0, 22 (31%)/23 (46%); peritoneal metastasis 38 (54%)/26 (52%); liver metastasis 15 (21%)/6 (12%); CLDN18.2 high 31 (44%)/25 (50%). In the NIVO group, patient characteristics did not differ between CLDN18.2 high and low except for peritoneal metastasis (25 [81%]/22 [55%]). Nine patients (29%) were CLDN18.2 high with CPS≥1, and 14 (35%) were CLDN18.2 low with CPS≥1. OS from first-line chemotherapy did not differ between CLDN18.2 high and low in the non-NIVO group (median, 18.4 months [95%CI, 10.7-32.4] vs. 16.9 months [95%CI, 14.8-21.4], HR 0.94 [95%CI, 0.50-1.78], p=0.847). In the NIVO group, OS from first-line chemotherapy and OS and PFS after starting NIVO did not differ between CLDN18.2 high and low; however, patients with CLDN18.2 high and CPS≥1 had longer OS after starting NIVO (median, 14.8 months [95%CI, 4.2-NR] vs. 3.6 months [95%CI, 2.0-6.9], HR 0.27 [95%CI, 0.11-0.68], p=0.012) and PFS after starting NIVO (median, 3.5 months [95%CI, 0.7-NR] vs. 1.7 months [95%CI, 1.1-3.1], HR 0.38 [95%CI, 0.15-0.97], p=0.033) than those with CLDN 18.2 high and CPS&lt;1. Patients with CLDN18.2 high and CPS≥1 had a trend of longer OS from first-line chemotherapy than those with CLDN 18.2 high and CPS&lt;1 (median, 37.4 months [95%CI, 11.1-NR] vs. 14.8 months [95%CI, 9.4-31.2], HR 0.47 [95%CI, 0.17-1.31], p=0.12). In the CLDN18.2 low group, OS and PFS did not differ between CPS≥1 and &lt;1. Conclusions: With CLDN18.2 high, CPS≥1 was associated with longer survival in AGC treated with NIVO.
Lack of hierarchical survival prognosis in AJCC staging for colon cancer: Implications for future summary stage classification.
Authors: Neal Bhutiani, Chung-Yuan Hu, Bryan E. Palis, Joseph Cotler, Qian Shi, Richard M. Goldberg, Mary Kay Washington, Heidi Nelson, Scott Steele, George J. Chang
Journal: Journal of Clinical Oncology (2023)

256 Background: Current staging for colon cancer utilizing the American Joint Committee on Cancer TNM framework stratifies disease into groups according to how advanced the disease is and provides important standardized, individual prognostic information. Ideally, staging systems should exhibit hierarchical logic, with increasing stage reflecting worse prognosis. We sought to evaluate hierarchy within the 8 th edition AJCC staging system for colon cancer. Methods: All patients with primary colon (including rectosigmoid) cancer diagnosed 2010-2017 were identified from the National Cancer Database (NCDB). Patients were only included if they carried a histologic diagnosis of invasive primary (non-recurrent) cancer, underwent radical surgery, and had complete pathologic staging data (T, N, M category data). Patients with missing follow-up data were excluded. Kaplan-Meier curves were used to assess overall survival by AJCC 8 th edition pathologic summary stage group to determine whether staging was hierarchical for colon cancer. Multivariable modeling and log likelihood ratio test was then used to identify relative contributions of T and N variables to overall survival. Results: Among 270,584 colon cancer patients, pathologic staging was noted to be hierarchical by T category alone and by N category alone. However, summary staging was non-hierarchical in both instances. Multivariable modeling confirmed the AJCC non-hierarchy issue (colon HRs: 1, 1.54, 2.62, 2.60, 1.02, 2.15, and 4.38 for stage 1 as reference, 2a, 2b, 2c, 3a, 3b, 3c respectively). Multivariable modeling demonstrated that high T category (T4a, T4b) conferred the greatest risk of mortality based on hazard ratio (T4a HR 2.76, T4b HR 3.04), while high T category as well as high N category (N2a, N2b) contributed substantially to the survival model based on z-score. Further modeling assessing the predictive power of T and N category with respect to overall survival demonstrated that T category more strongly predicted overall survival than N category in colon cancer (likelihood chi-square test statistic pT:7009 vs pN:3586). Conclusions: Hierarchy in survival based on AJCC summary stage was not observed for patients with stage II-III colon cancer resulting in a paradoxical better observed survival with some stage III cancer subgroups compared to stage II cancer subgroups. High T category appears to more significantly impact survival than N category for patients with N0-N1 disease, while high N category appears more important for patients with T1-3 disease. Future revisions of the AJCC staging system should account for the differential impact of T and N category identified herein to more accurately confer prognostic information.
Proposal of a coagulation score to predict postoperative survival of patients undergoing neoadjuvant therapy followed by subtotal esophagectomy for squamous cell carcinoma of the esophagus.
Authors: Fumitake Sugiyama, Dai Shimizu, Mitsuro Kanda, Chie Tanaka, Hideki Takami, Yoshikuni Inokawa, Norifumi Hattori, Masamichi Hayashi, Goro Nakayama, Michitaka Fujiwara, Yasuhiro Kodera
Journal: Journal of Clinical Oncology (2023)

448 Background: Despite advances in multimodality treatment of esophageal squamous cell carcinoma (ESCC), the recurrence rate after curative resection remains high. Assessment of the risk of disease recurrences after curative resection of ESCC will be helpful for optimization of individual patient management. The close association between coagulation status and progression of malignant tumors has been previously reported. We herein sought to identify sensitive prognostic factors in ESCC by combining multiple coagulation markers. Methods: A total of 200 patients who underwent curative subtotal esophagectomy after neoadjuvant treatment for ESCC between January 2012 and December 2020 were included in the analysis. We retrospectively evaluated the correlation of preoperative plasma D-dimer (upper limit of normal, 1.0 μg/mL), fibrinogen (upper limit of normal, 350 mg/dL) levels and the coagulation score, which is calculated by combining levels of D-dimer and fibrinogen, with postoperative prognosis. The coagulation score was determined as follows. 0, neither D-dimer nor fibrinogen were elevated; 1, either D-dimer or fibrinogen was above the upper limit of normal; 2, both were elevated. Results: There was no significant difference in postoperative recurrence-free survival between the high and low groups for either preoperative D-dimer alone or preoperative fibrinogen alone. 59 patients (29.5%), 99 patients (49.5%) and 42 patients (21%) were categorized into coagulation score 0, 1 and 2, respectively. Patients in the coagulation score 1-2 group had a significantly shorter recurrence-free survival time than those in the coagulation score 0 group (hazard ratio 1.99, P = 0.0223). Conclusions: The coagulation score combining with plasma D-dimer and fibrinogen levels was suggested to be a simple predictor of postoperative recurrences in patients undergoing curative subtotal esophagectomy after neoadjuvant treatment for ESCC.